SLAMF receptors and their adapters SAP and EAT-2 play a major role in human and mouse innate and adaptive immune response. Investigators in this Program Project have discovered that in mice several of these receptors either positively or negatively regulate the development of autoimmunity, including lupus related pathology. Excitingly, preliminary studies have revealed deviations in signaling pathways initiated by several SLAMF receptors in immunocytes isolated from patients with systemic lupus erythematosus (SLE). The overall hypothesis of Project #1 is that the mouse receptors Slamf3, 5, and 6 and their isoforms govern immune responses involved in the pathogenesis of murine lupus. The experiments that are designed to test this hypothesis are grouped as follows: Specific Aim#1: Testing the hypothesis that the three Slamf6 receptor isoforms initiate distinct positive and negative regulatory pathways to lupus. Specific Aim #2: Testing the hypothesis that the Slamf5 receptor governs signaling in T and B cells and DC during the pathogenesis of mouse lupus. Specific Aim #3: Testing the hypothesis that Slamf3 receptor initiated signaling controls autoantibody production.